On Sunday at ACR Convergence 2021, the Accelerating Medicines Partnership (AMP) SLE Consortium presented the most detailed overview to date of the molecular landscape of systemic lupus erythematous and lupus nephritis. The consortium’s findings offer early hints of potential diagnostic and therapeutic implications.
“We are not ready to make any conclusions, but we have some preliminary thoughts. We are just beginning the analysis,” said Betty Diamond, MD, Director and the Ralph Nappi Professor of Autoimmune Diseases at the Feinstein Institutes for Medical Research and Professor of Molecular Medicine and Professor of Medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell.
The AMP RA/SLE Program, which is overseen by the National Institutes of Health, links academia, industry, and nonprofit groups in an effort to develop new ways to identify and validate promising biological targets for diagnostics and drug development. The program’s goal is to generate pre-competitive, disease-specific data that will be publicly accessible to the broad biomedical community for further research. AMP’s initial research focus is RA and lupus, but the goal is to expand to related autoimmune diseases in the future.
Dr. Diamond was one of three AMP researchers to review the consortium’s early findings during the session Accelerating Medicines Partnership—SLE: Phase 2 Results, which was originally presented November 7 and can be viewed by registered meeting participants through March 11, 2022. She provided an overview of single cell RNA-Seq results for immune cells in the kidney among lupus patients with nephritis compared to healthy controls.
The AMP SLE/LN cohort includes 161 LN patients and 30 living donor controls with healthy kidneys. The cohort was deliberately diverse — 29% Hispanic, 31% white, 44% Black, 14% Asian, and 11% other or unknown — with a mean age of 36. Most of the cohort, 87%, was female, and there was broad representation by ISN class. Researchers worked with kidney tissue biopsies as well as blood and urine samples. All individuals were followed for one year from baseline.
The primary goal of the research is to identify molecular signatures in kidney tissue that correlate with response, Dr. Diamond said.
Immune cells segregated into 21 distinct clusters, she reported. A high prevalence of B cells was associated with response, which correlates with other recent findings. A lower chronicity index at baseline was associated with complete response at week 52.
All of the immune cell types studied — myeloid, T, B, and plasma cells — showed markedly different clusters and distribution between patients and controls, Dr. Diamond continued. None of the patient myeloid clusters were associated with response, but some clusters were associated with activity and chronicity. Responders showed fewer T + NK cells and cytotoxic T lymphocytes versus nonresponders, while a higher number of CD4+ cells was associated with chronicity.
Healthy kidneys showed few to no B cells, while patient samples were enriched in B cells. But there were no associations between B-cell clusters and outcome, Dr. Diamond said. Plasma-cell clusters showed only weak associations with outcome, she added.
James Lederer, PhD, Research Associate at Brigham and Women’s Hospital and Associate Professor of Surgery at Harvard Medical School, discussed mass cytometry (CyTOF) findings from blood samples. CyTOF uses antibodies tagged with rare earth metals, unlike flow cytometry, which uses fluorescent-tagged antibodies or binding reagents.
CyTOF was used to explore NK, T, B, myeloid, and granulocyte cells using 48 markers. Not surprisingly, all cell types showed different density and clustering results between SLE patients and healthy controls.
SLE patients showed significantly more Treg, naïve CD4, and cytotoxic CD8 cells compared to controls, Dr. Lederer reported. Patient samples were also enriched for age-associated B cells and a subset of plasmablasts.
Myeloid cells from SLE patients showed significant expression of Siglec-1, which drives a dramatic increase in monocyte density, Dr. Lederer said. Siglec-1/Sialoadhesin is an IgSF adhesion receptor involved in innate self/nonself recognition.
NK cells showed enrichment for CD8+, double negative T, cytotoxic T, and proliferating CD38++ cells, Dr. Lederer said.
“Deeper analysis of these data is ongoing,” he noted. “We will be including clinical features, treatments, and longitudinal changes in the future.”
Renal epithelial and stromal cell association neighborhoods show similarly dramatic differences between patients and healthy controls, reported Joseph Mears, BA, from the University of Michigan Medical Scientist Training Program. Different subsets of proximal tubule (PT) cells are associated with certain clinical and histological variables, he explained.
Among proximal and descending thin limb cells, for example, an expansion of PT3 cells is associated with complete response, while PT4 and DTL cell subsets are associated with nonresponse and higher chronicity. Patients with membranous LN have a higher relative abundance of PT3 cell subsets, while patients with proliferative LN have a higher abundance of PT4 and PT11 cell subsets. Healthy controls, by contrast, show an expansion of PT2 cell subsets, Mears said.
There are similar differences in stromal cells between patients and controls, he continued. LN patients show a depletion of vascular smooth muscle cells, while glomerular parietal epithelial cells, myofibroblasts, and peritubular endothelial cells are associated with increased chronicity.
“Epithelial and stromal cells are responding to the disease environment, but it is not yet clear if these changes are markers of response or are somehow involved in response,” Mears said.
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